Vascular endothelial growth factor (VEGF or VEGF-A) is a powerful vascular growth factor and is important for maintaining glomerular health. Clinically, an anti-VEGF state induces glomerular injury. For example, excess placental production of soluble Fms-like tyrosine kinase (sFLT1), a decoy receptor for VEGF, causes preeclampsia. Moreover, patients treated with VEGF inhibitors show glomerular pathologies and hypertension. Recently, Wewers et al. report a comprehensive review on the role of circulating sFLT1 in kidney diseases other than preeclampsia (1).
The kidney vasculature is particularly dependent on VEGF-VEGF receptor 2 (VEGFR2) signaling for its development and maintenance (1, 2). Podocyte-derived VEGF is critical for glomerular health, and tubular epithelial cell-derived VEGF is essential for developing peritubular capillaries. Although downregulation of VEGF signaling causes glomerular injury, excess VEGF is also detrimental to renal pathologies, including diabetic nephropathy (1). Therefore, VEGF expression must be regulated tightly for healthy glomerular and vascular functions, and the role of sFLT1 reflects the specific role of VEGF in each condition. Importantly, sFLT1 exerts its function locally and systemically. sFLT1 can be introduced into circulation and inhibits the proangiogenic function of VEGF in remote organs. sFLT1 can also control cellular functions locally by modulating local VEGF availability and directly activating intracellular signaling pathways independent of VEGFR signaling (1, 2).
To summarize the results of clinical studies testing the roles of circulating sFLT1 in multiple kidney diseases, the authors selected peer-reviewed articles published between 2009 and 2020, which investigated the association of sFLT1 and kidney function in chronic kidney disease, acute kidney injury (AKI), and kidney transplantation. Most studies show that the elevated circulating sFLT1 level is associated with adverse outcomes, such as lower estimated glomerular filtration rate (eGFR), slower recovery from AKI, and delayed graft function. However, one report suggests that a high level of sFLT1 could be more beneficial than harmful in coronary artery disease in patients with kidney disease (Figure 1) (1). Finally, the authors discuss several unanswered questions that need to be addressed before considering therapeutic removal of circulating sFLT1. For example, it is essential to answer whether sFLT1 is a pure biomarker of metabolic disturbances, or its elevation is harmful and causing disease. In summary, this review establishes the status quo for future mechanistic and clinical studies to better understand the role of sFLT1 in kidney diseases.
Wewers TM, et al. Circulating soluble Fms-like tyrosine kinase in renal diseases other than preeclampsia. J Am Soc Nephrol 2021; 32:1853–1863. doi: 10.1681/ASN.2020111579
Bartlett CS, et al. Vascular growth factors and glomerular disease. Annu Rev Physiol 2016; 78:437–461. doi: 10.1146/annurev-physiol-021115-105412